The control of body weight is a complex process that at present is incompletely understood. It is multifactorial and is influenced by appetite, food ingestion and excretion, energy utilisation and expenditure. A number of soluble mediators are known to be involved in regulating various aspects of this process and include hormones and cytokines such as leptin, ghrelin, melanocortin, agouti-related peptide, and neuropeptide Y (NPY). Normal weight control is important to good health and obesity especially, may greatly increase morbidity and mortality in individuals. Lower than average weight can also be problematic, and in developed societies, where sufficient food is available, this is more frequently due to diseases including some chronic inflammatory disorders, eating disorders such as anorexia nervosa, and cancer. Especially in the late stages of cancer, cachexia is common (occurring in most terminally ill cancer patients), and is responsible for about a quarter of all cancer-related deaths.
Some years ago, the present applicant cloned and characterised a novel human TGF-β superfamily cytokine that was named macrophage inhibitory cytokine-1 (MIC-1) (1-7), but has since also become known as prostate derived factor (PDF), placental bone morphogenetic protein (PLAB), and growth/differentiation factor-15 (GDF-15) (7). Under resting conditions, placenta is the only tissue expressing large amounts of MIC-1 (7), but epithelial cells in a wide variety of other organs also normally express small amounts of MIC-1 mRNA. This low level of normal MIC-1 expression is, however, dramatically increased in malignancy, inflammation and injury (7, 8-11), the increase being induced by a wide variety of cell stress and activation factors, and is mediated intracellularly, particularly by the transcription factor p53 and EGR-1 (12-15). In particular, increased MIC-1 expression has been strongly linked to breast, prostate, pancreatic and colon cancers (9-11, 17, 18), and in a recently published study (20) of several hundred patients with colonic polyps or colon cancer, the present applicant showed that elevation of serum levels of MIC-1 occurs in a progressive stepwise manner, reflecting colon cancer pathogenesis, with progression from normal to benign and then to dysplastic colonic polyps and finally colon cancer. This observation, along with results from other studies (15, 17, 19, 21), suggests that MIC-1 has an important role in tumour progression, by inducing significant paracrine effects modulating the tumour environment.
In work leading to the present invention, it had been observed that the serum levels of MIC-1 of patients in the late stages of one of the abovementioned epithelial cancers (eg serum levels of 10 to 50 ng/ml or more), correlated with serum levels in mice which were over-expressing MIC-1 and which showed marked weight loss. It was therefore proposed that the cachexia commonly exhibited in patients with cancer associated with increased MIC-1 expression, is due to the over-expression of MIC-1 and that by inhibiting that expression (eg with anti-MIC-1 antibodies), it would be possible to reverse or reduce the severity of the weight loss.